P

Figure 5.8 Gastric pH after a meal. Electrode positions are G1=5 cm, G2=10 cm and G3=15 cm below the gastro-oesophageal sphincter causes rapid acid production, but mixing in this region is poor, so that the extended buffering effect of the food is observed. As the food moves into the antrum, the vigorous mixing not only reduces particle size of the food, but mixes it with the gastric acid which was produced higher in the stomach. The pH in the antrum remains low, despite the fact that there are no parietal cells in this region, since much of the food has been neutralized while stored in the body of the stomach (note: the small peak seen after 30 minutes was due to the administration of 50 ml of water for a separate phase of the experiment, and should be ignored).

Acid secretion is increased after hot or cold meals even though temperature of the meal per se does not alter gastric emptying. It takes significantly longer for cold meals to be brought to body temperature than hot meals2. Content of the meal also affects gastric pH; for example, a pure carbohydrate meal given as a pancake has no detectable effect on acidity3, while a protein meal of similar calorific value has a significant buffering effect4. A liquid meal, rather than a mixed phase meal, with a balance of carbohydrate and protein has a strong buffering effect but the pH rapidly returns to basal levels as the liquid is emptied. The situation is complicated by feedback effects; for example pepsin normally hydrolyses proteins to peptides and amino acids, which are potent secretagogues, and increase the acidification of gastric contents. However pepsin is inactivated above pH 5, so a large meal which raises the pH above this value will prevent the production of these substances, and peak gastric acid secretion will be reduced.

Circadian rhythm of acidity

A circadian rhythm of basal gastric acidity is known to occur with acid output being highest in the evening and lowest in the morning (Figure 5.9)5. The daytime patterns of gastric pH vary greatly between individuals, in part due to the differences in the composition of meals and the variable responses of acid secretion and gastric emptying. However, nocturnal patterns of gastric acidity are very similar with very low pHs between midnight and early morning3. The later in the day the evening meal is taken, the later the nocturnal peak of acidity occurs6; it is therefore important to standardise the time for the evening meal when comparing the nocturnal effects of anti-secretory drugs.

Figure 5.9 Circadian variation in gastric acidity

Night-time transient increases in pH can be detected by electrodes placed in the antrum and body of the stomach. They have been interpreted as evidence of duodeno-gastric reflux flowing from the antrum into the body7 since the increase often occurs in the fundus before that in the body. The same phenomenon may explain the observation that if a group of subjects are kept awake at night, the pH of the gastric juice is observed to rise compared to sleeping levels, which may be due to increased duodeno-gastric reflux in subjects who are denied sleep.

pH and gender

Healthy women secrete significantly less basal and pentagastrin-stimulated acid than men with a median 24 h integrated acidity of 485 mmol.h-1 versus 842 mmol.h-1. In a sample of 365 healthy subjects, the average basal pH was 2.16±0.09 for men and 2.79± 0.18 in women8.

pH and age

It has always been assumed that gastric acid secretion decreases with age, however this has shown not to be true. A group of healthy subjects with a mean age of 51 years (range 4471 years) had a higher basal acid production than a group with a mean age of 33 years (range 23-42 years)9. The age related increase in secretion was greater in men than women and was not correlated with height, weight, body surface area or fat-free body mass, or by the increased incidence of Helicobacter pylori infection.

Occasionally, babies are intubated for the purposes of investigating oesophageal reflux, but results are sparse in older children. In twelve healthy children aged 8-14 years, the mean fasting gastric pH was 1.5 and the duodenal pH was 6.4. The pH gradually rises down the small intestine reaching a peak value of 7.4 in the distal ileum10. The pH dropped to 5.9 in the caecum but increased to 6.5 in the rectum. In 11 healthy adults, the median pH was 7.0 in duodenum, dropped to pH 6.3 in the proximal part, but rose to 7.3 in the distal part of the small intestine11. These values are quite similar and allay fears that, for example, sustained-release or enteric coated dose forms evaluated in adults may not work correctly in children.

pH and smoking

Daytime intragastric acidity is higher in smokers (median pH 1.56) compared to non-smokers (median pH 1.70); however, there is no significant difference in 24 hour or night time pH12.

GASTRIC MOTILITY The fasted state

The stomach will revert to the fasted pattern of motility in the absence of digestible food, or when it is empty (Figure 5.10). After a meal, the digestible food will have been processed to chyme and passed to the small intestine leaving a residue of mucus and undigested solids. These remain in the stomach until the small intestine has finished absorbing nutrients from the chyme i.e. approximately 2 h after the last of the digestible food has left the stomach. At this point the digestive phase of activity ceases and is replaced by the interdigestive phase, which is also the normal resting condition of the stomach and small intestine. All gastric residues which the stomach has failed to process to chyme are removed in this phase, the migrating myoelectric complex (MMC) or so-called 'housekeeper contractions'. The MMC removes debris from the stomach by strong contractions against an open pylorus.

Figure 5.10 The migrating myoelectric complex

Starting from a state in which the stomach and small intestine show no motor activity (Phase I), the activity front begins simultaneously in the antrum and duodenum producing a series of mixing contractions which build up over a period of 60-90 minutes (Phase II). These end in a series of powerful circular peristaltic waves which sweep from the site of origin down the entire small bowel to the caecum emptying all the large solid particles from the stomach and small intestine (Phase III). The waves then subside to the resting phase. The whole cycle repeats every two hours until a meal is eaten, when they are immediately interrupted to initiate the digestive phase of motility. The peristaltic waves can also be halted by an intravenous infusion of a hormone, motilin.

Gastric emptying of the basal gastric secretion occurs even during fasting to prevent accumulation of fluid, as there is very little net absorption by the gastric mucosa.

The fed state

The adult capacity of the stomach is about 1500 ml. The average (western) daily intake of food and drink is 3 to 4 kg, and it is estimated that another 5 litres of fluids such as saliva, gastric juice, pancreatic juice and other body liquids are added to this. The greatest secretory activity occurs in the stomach within the first hour of eating and the volume of gastric juices produced may be up to twice that of the meal.

The uppermost third of the stomach, or fundus, adapts to the varying volume of ingested food by relaxing its muscular wall, holding the food while it undergoes the first stages of digestion. The adaptive process allows it to accommodate the ingested food without increasing intragastric pressure.

The stomach not only elicits a fed pattern of motility in response to the presence of food with calorific value, but it will also respond to the presence of a large quantity of small particle size indigestible material, suggesting that gastric distention is also a contributory factor13. Indigestible material of small diameter (1-3 mm) will elicit the fed pattern of motor activity in dogs, and the duration of postprandial antroduodenal motility patterns can be influenced solely by the size of a meal which comprises only of indigestible material.

The mixing, grinding and emptying of food all occur together. The dispersion of food is more a mechanical process than an enzymatic one. Mixing and grinding are carried out by a series of peristaltic waves which originate in mid-body as a shallow indentation and gradually deepen as they progress toward the duodenum. The velocity of the wave increases until the final 3 to 4 cm of the antrum are reached, at which stage the antrum and pylorus appear to contract simultaneously. This is often called antral systole. Liquids and solids within the distal antrum are compressed as the antral wave deepens. The wave does not occlude the lumen and hence liquid and suspended particles are retropelled through the wave, but larger and denser solids are trapped ahead of the constriction. Once the pylorus has closed, the antral systole grinds and then retropels the solids into the proximal antrum (Figure 5.11). The grinding action, combined with the shear forces produced during retropulsion, reduce the particle size and mixes the particles with gastric juice. The motion and acid-pepsin digestion accounts for the physical breakdown of solid food in this region. The rate of emptying from the human stomach decreases if the ingested solid food is composed of larger masses. Solids are only emptied after they are ground to particles smaller than approximately 1 mm, and the larger, harder particles will take longer to reach this size.

Tonic or sustained motor activity decreases the size of the lumen of the stomach, as all parts of the gastric wall seem to contract simultaneously. It is this type of activity that accounts for the stomach's ability to accommodate itself to varying volumes of gastric content. Mixing contractions and peristaltic contractions are superimposed upon the tonic contraction, which is independent of the other contractions. Both the mixing and the peristaltic contractions occur at a constant rate of three per minute when recorded from the gastric antrum. This rate is now recognised as the basic rhythm, although some drugs are capable of abolishing both types of contractions or of stimulating the strength of contractions. The distension of the body of the stomach by food activates a neural reflex that initiates the activity of the muscle of the antrum.

About twice per minute between 1 and 5 ml of antral contents escape into the duodenum, and decrease the duodenal pH. Emptying from the pylorus occurs in discrete episodes of 2 to 5 seconds only, and the majority of these occur as the terminal antrum,

Figure 5.11 Grinding and mixing action of the antral mill Note retropulsion ot particles i.e. sieving pylorus and duodenum relax at the start and end of each peristaltic cycle14. Transpyloric flow ceases approximately 2 seconds before the antral systole occurs14 15. It was assumed that the particle size cut-off was produced by the narrow pyloric diameter, but neither pyloroplasty nor pylorectomy alters the size distribution of food passed into the duodenum16 and the antrum alone can selectively retain solids in the absence of the pylorus. The pylorus appears to be wide open, having an aperture larger than 5 mm, for approximately 15 to 20% of the time17. The length of time for which the pylorus is wide open does not completely determine the emptying rate of liquids because the duodenum also seems to apply a braking mechanism. The periodic opening of the pylorus during the fed phase of motility can explain how some large particles, including intact large fragments of tablets, can be emptied during this cycle.

Solids and liquids do not empty from the stomach together as a homogeneous mass. Liquids empty according to the pressure gradient between the stomach and duodenum, with isotonic liquid meals emptying more rapidly than hypotonic or hypertonic mixtures. The liquid component of a meal empties exponentially, but the emptying of solids is linear after a variable lag time (Figure 5.12). The lag phase is dependent upon the size of the food particles in the stomach. Larger particles require a longer period of digestion to break them down into a size suitable to exit through the pylorus. Small indigestible solids of between 1 to 5 mm in diameter are progressively emptied during the whole postprandial period even before liquid emptying is completed. Certain liquids and solids can be clearly seen as two separate layers on magnetic resonance images (Figure 5.13). Interestingly, during episodes of heartburn or gastro-oesophageal reflux, food and acid are refluxed into the oesophagus independently of each other18. It is likely that this occurs because the food forms a central core in the body of the stomach. As gastric acid is secreted around the outside of the food mass, it is only mixed effectively with the food in the antrum. Refluxed material originates largely from the upper part of the stomach where mixing is irregular.

Receptors in the duodenal bulb detect the calorific value and hydrogen ion concentration of the chyme causing relaxation of the lower part of the duodenum, and allowing gastric emptying to start. During a duodenal contraction, the pressure in the

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